SREBP‐1c Modulates Metabolic Profile of Mice Fed a Western Diet

Abstract

Sterol regulatory element binding proteins (SREBPs) are major regulators of fatty acid and cholesterol synthesis. The objective of this study was to investigate global blood and liver metabolic profile in wild-type (WT) and SREBP-1 knockout (KO) mice exposed to various lipid-containing diets. Female WT and KO mice were randomly assigned to 4 diet groups: low fat diet (LF); high saturated fat diet (HF); high cholesterol diet (HC); and high saturated fat and high cholesterol diet (HF-HC). After 12 wks of diet, blood and liver tissues were analyzed by 1H-NMR. Only a slight increase in blood circulating fatty acids, triacylglycerol (TAG) and cholesterol were seen in the WT mice on the HF-HC diet (total lipids in LF 18 umol/mL vs 23 in HF-HC, p<0.05). In the KO mice this increase was entirely abolished (15 umol/mL). A significant increase in blood glucose was seen in the WT HF-HC group, with no changes in the KO mice. The liver metabolic profile showed significantly higher response to dietary modification. Cholesterol, TAG, fatty acids, and total hepatic lipids were significantly increased in the WT HF-HC group (total lipids: 132 umol/mL in LF vs. 690 in HF-HC), while glucose and glutathione levels were reduced. In the KO mice less lipid were accumulated in the liver 459.76 umol/mL in HF-HC diet and no changes in glucose or glutathione were observed. Conclusion: Hepatic metabolism is most sensitive to high-lipid diet resulting in highly increased hepatic lipid content, decreased glucose transport and decreased antioxidative defense. In the mice lacking the SREBP-1c gene, less lipid abnormalities were observed with no defects in carbohydrate transport or endogenous antioxidant levels.